Implantable Graft to Close a Fistula

ABSTRACT

An implantable graft, which may be inserted into a fistula tract to occlude the primary opening of the fistula, is provided. To prevent unintentional displacement of the graft or extrusion of the graft from the fistula of a patient, the graft may be provided with a cap that extends laterally from at least one end of the body of the graft, where the cap may be integral with the body of the graft, attachable to at least one end of the body of the graft, and/or moveable along the body of the graft. The graft may also have a tail that extends from one end of the body of the graft to assist in placement of the graft in a fistula tract. The graft may be an integral unit made of a single material, such as a heterograft material, or may include distinct components made of the same or different materials. Methods for closing a fistula tract are also provided.

RELATED APPLICATIONS

The present patent document claims the benefit of the filing date under35 U.S.C. §119(e) of Provisional U.S. Patent Application Ser. No.60/692,694, filed Jun. 21, 2005, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates generally to medical devices and inparticular aspects to medical grafts and methods for treating fistulas.

BACKGROUND OF THE INVENTION

A variety of abnormal passages called fistulas can occur in humans. Suchfistulas may be caused by, for example, an infection, a congenitaldefect, inflammatory bowel disease (such as Crohn's disease),irradiation, trauma, neoplasia, childbirth, or a side effect from asurgical procedure.

Some fistulas occur between the vagina and the bladder (vesico-vaginalfistulas) or between the vagina and the urethra (urethro-vaginalfistulas). These fistulas may be caused by trauma during childbirth.Traditional surgery for these types of fistulas is complex and not verysuccessful.

Other fistulas include, but are not limited to, tracheo-esophagealfistulas, gastro-cutaneous fistulas, fistulas extending between thevascular and gastrointestinal systems, and any number of anorectal(ano-cutaneous) fistulas, such as fistulas that form between theanorectum and vagina (recto-vaginal fistulas), between the anorectum andbladder (recto-vesical fistulas), between the anorectum and urethra(recto-urethral fistulas), or between the anorectum and prostate(recto-prostatic fistulas). Anorectal fistulas can result from infectionin the anal glands, which are located around the circumference of thedistal anal canal forming an anatomic landmark known as the dentate line1, shown in FIGS. 1 and 2. Approximately 20-30 such glands are found inhumans. Infection in an anal gland can result in an abscess. Thisabscess can then track through soft tissues (e.g., through or around thesphincter muscles) into the perianal skin, where it drains eitherspontaneously or surgically. The resulting void through the soft tissueis known as a fistula. The internal or inner opening of the fistula,usually located at or near the dentate line, is known as the primaryopening 2. The primary opening is usually the high pressure end of afistula. Any external or outer openings, which are usually located inthe perianal skin, are known as the secondary openings 3. The secondaryopenings are usually the low pressure end of a fistula.

FIGS. 1 and 2 show examples of the various paths that an anorectalfistula may take. These paths vary in complexity. Fistulas that take astraight line path from the primary opening 2 to the secondary opening 3are known as simple fistulas 4. Fistula that contain multiple tractsramifying from the primary opening 2 and have multiple secondaryopenings 3 are known as complex fistulas 5.

The anatomic path that an anorectal fistula takes is classifiedaccording to its relationship to the anal sphincter muscles 6, 7. Theanal sphincter includes two concentric bands of muscle: the inner, orinternal, sphincter 6 and the outer, or external, sphincter 7. Fistulaswhich pass between the two concentric anal sphincters are known asinter-sphincteric fistulas 8. Those which pass through both internal 6and external 7 sphincters are known as trans-sphincteric fistulas 9, andthose which pass above both sphincters are called supra-sphinctericfistulas 10. Fistulas resulting from Crohn's disease usually ignorethese anatomic paths, and are known as extra-anatomic fistulas.

Many complex fistulas contain multiple tracts, some blind-ending 11 andothers leading to multiple secondary openings 3. One of the most commonand complex types of fistulas is known as a horseshoe fistula 12. Inthis instance, the infection starts in the anal gland (the primaryopening 2) at or near the twelve o'clock location (with the patient inthe prone position). From this primary opening, fistulas passbilaterally around the anal canal, in a circumferential manner, forminga characteristic horseshoe configuration 12, as illustrated in FIG. 2.Multiple secondary openings 3 from a horseshoe fistula 12 may occuranywhere around the periphery of the anal canal, resulting in a fistulatract with a characteristic horseshoe configuration 12.

One technique for treating a fistula is to make an incision adjacent theanus until the incision contacts the fistula and then excise the fistulafrom the anal tissue. This surgical procedure tends to sever the fibersof the anal sphincter, and may cause incontinence.

Another technique for treating a fistula involves passing a fistulaprobe through the tract, in a blind manner, using primarily only tactilesensation and experience to guide the probe. Having passed the probethrough the fistula tract, the overlying tissue is surgically divided.This is known as a fistulotomy. Because a variable amount of sphinctermuscle is divided during the procedure, fistulotomy may result inimpaired sphincter control or even incontinence. Alternative methods andinstruments, such as coring-out instruments (See, e.g., U.S. Pat. Nos.5,628,762 and 5,643,305), may make the fistula wider and more difficultto close.

Yet another technique for treating a fistula involves draining infectionfrom the fistula tract and maturing it prior to a definitive closure orsealing procedure by inserting a narrow diameter rubber drain, known asa seton, through the tract. This is usually accomplished by inserting afistula probe through the outer (secondary) opening 3 and gently guidingit through the fistula, and out through the inner (primary) opening 2. Aseton, thread or tie is then affixed to the tip of the probe, which isthen withdrawn back out of the tract, leaving the thread in place. Theseton may then be tied as a loop around the contained tissue and leftfor several weeks or months.

An additional method of closing the primary opening is by surgicallycreating a flap of skin, drawing this flap of skin across the opening,and suturing the flap in place. This procedure (the endo-anal flapprocedure) closes the primary opening, but is technically difficult toperform, is painful for the patient, and is associated with a highfistula recurrence rate.

More recently, methods have evolved to inject sclerosant or sealant(e.g., collagen or fibrin glue) into the tract of the fistula to blockthe fistula. Such sealants are described in Rhee, U.S. Pat. No.5,752,974, for example. Usually, multiple injections are required toclose the fistula by this method. In some instances, closure of afistula using a sealant may be performed as a two-stage procedure,comprising a first-stage seton placement, followed by injection of thefibrin glue several weeks later. This procedure reduces residualinfection and allows the fistula tract to “mature” prior to injecting asealant. Injecting sealant or sclerosant into an unprepared or infectedfistula as a one-stage procedure can cause a flare-up of the infectionand even further abscess formation.

Even more recently, methods of treating fistulas by placing a graft inthe fistula tract have been discovered, as described in co-pendingapplication serial number 11/040,996 (Armstrong), U.S. PatentApplication Publication No. 2006/0074447, hereby incorporated byreference in its entirety. Such grafts may have a tapered body with awider proximal end and a thinner distal end, as shown in FIG. 3. Thegraft may be pulled through the primary opening until the head portionof the graft is lodged in the primary opening, where it is retained inthe same manner as a plug in a hole. The graft may also be secured bysuturing the graft to the tissue of the patient, for example. Despitethe tapering design of these grafts, they may still be subject todisplacement or extrusion from the patient when excessive force isapplied to the proximal end of the graft during exertion or straining,especially in the case of the wide fistulas that are common in patientswith Crohn's disease or recto-vaginal fistulas. Although suture may beused to further secure the graft in some instances, it may be difficultto suture the proximal end of the graft to the tissues of a patientwhere surgical access to the primary opening of the fistula is limited,such as in anorectal and recto-vaginal fistulas where the primaryopening is often located high in the rectum. Even if suturing the graftto the tissues of a patient is possible, the suturing may be painful forthe patient.

Other techniques for treating fistulas are described in U.S. applicationSer. No. 11/415,403, titled “VOLUMETRIC GRAFTS FOR TREATMENT OF FISTULAEAND RELATED METHODS AND SYSTEMS” (Cook Biotech Incorporated), filed May1, 2006, which claims priority to U.S. Provisional Application Ser. No.60/676,118, filed Apr. 29, 2005; and U.S. Provisional Application (Ser.No. not yet assigned), titled “FISTULA GRAFTS AND RELATED METHODS ANDSYSTEMS USEFUL FOR TREATING GASTROINTESTINAL FISTULAE” (Cook BiotechIncorporated), filed Jun. 21, 2006, naming F. Joseph Obermiller as theinventor, which are hereby incorporated by reference in their entirety.

There remains a need for improved and/or alternative medical products,methods, and systems that are useful for treating fistulas. The presentinvention addresses these needs.

SUMMARY OF THE INVENTION

One object of the present invention is to provide a new technique ofminimally invasive fistula closure. Another object is to provide asimplified technique that obviates the need for surgical fistulotomy andavoids surgical pain and the attendant complications of the procedure.Another object of the invention is to provide an accurate and completeclosure of a fistula, thereby preventing a recurrent or persistentfistula. Still another object of the invention is to provide a graftthat resists unintentional displacement or expulsion and to providemethods of closing a fistula where the graft is firmly secured withinthe fistula. Yet another object of the invention is to provide atechnique that involves no cutting or piercing of tissue, sphincterdamage, or incontinence.

The present invention may be used in any type of fistula. For example,the claimed devices and methods may be used to graft or occludetracheo-esophageal fistulas, gastro-cutaneous fistulas, anorectalfistulas, fistulas occurring between the vagina and the urethra orbladder, fistulas occuring between the vascular and gastrointestinalsystems, or any other type of fistula.

The present invention provides grafts and methods designed to simplifyimplantation of a graft in a fistula of a patient and to resistexpulsion of the graft from the patient during exercise or straining.The graft of the present invention may have a generally conical graftbody having a wider proximal end that tapers to a narrower distal end, agenerally cylindrical graft body, a sheet form graft body, or a graftbody having any other shape suitable for implantation within a fistula.The graft body or any portion of the graft body may have passagestherethrough and may have a central lumen for placement of a guidewire.

The graft of the present invention may include a cap in the form of adisc, cone, sphere, hemisphere, trumpet-shape, polygon, or any othersuitable shape. Desirably, the cap extends laterally from the headportion of the graft body and prevents migration of the graft and/orextrusion of the graft from the fistula. The cap may be integral withthe body of the graft or may be a separate structure that is attachableto the body of the graft in a non-permanent manner. The cap may bemoveable along the body of the graft or secured to the graft body usingany suitable method. For example, absorbable sutures may be passedthrough apertures in the cap to secure the cap to the graft body. Insome embodiments of the invention, after the sutures dissolve andsufficient time elapses for the graft to become firmly secured withinthe fistula tract (e.g. by incorporation of host tissue into the graft),the cap detaches from the graft and is released into the body.

The graft may also include an elongated tail extending from the end ofthe graft body opposite the end on which the cap is located. Such a tailfacilitates implantation of the graft within a fistula and eliminatesthe need for an initial seton placement step.

In another embodiment of the graft of the present invention, a secondcap is used to secure the end of the graft body opposite a first cap.The first cap may be used to prevent dislodgement of the graft in onedirection, and the second cap may be used to prevent dislodgement of thegraft in the opposite direction. In some embodiments, suture may bepassed through apertures in the first cap, through the body of thegraft, and then through apertures in the second cap, thereby securingthe caps to the graft body.

The graft of the present invention may be made of any suitablebiological or synthetic material. Desirably, the material elicits littleimmunological reaction, has some inherent resistance to infection, andpromotes tissue reconstruction (rather than complete absorption of thegraft into the surrounding tissue), thereby occluding the fistula. Thegraft may also incorporate one or more bioactive agents.

In certain embodiments of the present invention, the graft is made of amaterial receptive to tissue ingrowth. In such aspects, upon deploymentof the product in accordance with the present invention, cells from thepatient can infiltrate the material, leading to new tissue growth on,around, and/or within the graft. In some embodiments, the graftcomprises a remodelable material, such as small intestinal submucosa(SIS). In these embodiments, the material promotes and/or facilitatesthe formation of new tissue, and is capable of being broken down andreplaced by new tissue in such a way that the original fistula closureachieved by the implanted graft product is maintained throughout theremodeling process so as to eventually form a closure or substantialclosure with the new tissue.

The present invention also provides methods of treating fistula. In oneembodiment of the method of the present invention, a graft having agraft body, a cap that is integral with or detachable from the graftbody, and an elongated tail is inserted into the fistula tract until thecap abuts the primary opening of the fistula, the graft body extendsinto at least a portion of the fistula tract, and the tail protrudesfrom the secondary opening of the fistula. The cap may include aplurality of holes, such as those in a button, so that absorbable suturecan be inserted through the holes and used to secure the cap to thegraft body. The tail of the graft may be secured in place by anysuitable means of affixation, such as by suturing the tail to thetissues of the patient or by using a securing device, such as a secondcap or a bead with a central lumen, through which the tail may be passedand secured by crimping or suturing, thereby eliminating the need toplace sutures in the tissues of the patient and the correspondingdiscomfort to the patient. Any excess portions of the tail and/or graftmay then be trimmed. The cap maintains the graft body in the fistulatract and prevents it from being displaced or extruded during exertionor straining by the patient. After a period of time, the absorbablesuture attaching the cap(s) to the graft body dissolves, allowing thecap(s) to fall off and be passed out of the body. By this time the graftis firmly secured within the fistula tract.

Additional features and advantages of the present invention will beapparent to one of ordinary skill in the art from the drawings anddetailed description of the preferred embodiments below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows several possible anatomic courses taken by various forms ofanorectal fistula (longitudinal plane);

FIG. 2 shows a perineal view of a simple anorectal fistula and ahorseshoe fistula; and

FIG. 3 shows one embodiment of the graft body of the present invention.

FIG. 4 shows one embodiment of the graft of the present invention havinga generally conical graft body with an integral cap and an elongatedtail.

FIG. 5 shows another embodiment of the graft of the present inventionhaving a generally conical graft body with an attachable cap and anelongated tail.

FIG. 6 shows still another embodiment of the graft of the presentinvention having a generally cylindrical body with two attachable caps.

FIG. 7 is a perspective view of an another embodiment of the graft ofthe present invention.

FIG. 8 is a side view of the graft of FIG. 7 implanted within a patient.

FIG. 9 is a perspective view of an illustrative cap of the presentinvention.

FIG. 10A is a side view of another illustrative cap of the presentinvention.

FIG. 10B is a cross sectional view of the cap of FIG. 10A along the viewline 10 b-10 b shown in FIG. 10A

FIG. 11 is a perspective view of an illustrative sheet form graft bodyof the present invention.

FIG. 12 shows one embodiment of the graft of the present inventionhaving two caps connected to the graft body with suture.

FIG. 13 shows another embodiment of the graft of the present invention,similar to the embodiment of FIG. 12 but with an expandable cap.

FIG. 14 shows still another embodiment of the graft of the presentinvention having one cap attached to an end of the graft body andanother cap that is configured to slide along the graft body.

FIG. 15 shows the slideable cap of FIG. 14.

FIG. 16 shows the cap that is attached to one end of the graft body ofFIG. 14.

FIG. 17 is a top view of one embodiment of a medical product of thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

While the present invention may be embodied in many different forms, forthe purpose of promoting an understanding of the principles of thepresent invention, reference will now be made to the embodimentsillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of the invention is thereby intended. Any alterations andfurther modifications in the described embodiments and any furtherapplications of the principles of the present invention as describedherein are contemplated as would normally occur to one skilled in theart to which the invention relates.

Turning now to a discussion of the particular grafts, systems, andmethods of the present invention useful for treating fistulas,illustrative grafts of the invention are configured to block at leastthe primary opening of a fistula, i.e., the primary opening andpotentially one or more other segments of a fistula, for example, thefistula tract and/or any secondary openings. In this context, the term“fistula tract” is meant to include, but is not limited to, a void inthe soft tissues extending from a primary fistula opening, whetherblind-ending or leading to one or more secondary fistula openings. Also,as used herein, the terms “graft” and “plug” may be usedinterchangeably.

The graft of the present invention may be used to graft or occlude anytype of fistula, such as the types of anorectal fistula illustrated inFIGS. 1 and 2. Other types of fistula that may be occluded by thepresent invention include, but are not limited to, tracheo-esophagealfistulas, gastro-cutaneous fistulas, or fistulas occurring between thevagina and bladder (vesico-vaginal fistulas), between the vagina andurethra (urethro-vaginal fistulas), between the anorectum and vagina(recto-vaginal fistulas), between the anorectum and bladder(recto-vesical fistulas), between the anorectum and urethra(recto-urethral fistulas), between the anorectum and prostate(recto-prostatic fistulas), or between the vascular and gastrointestinalsystems.

In certain embodiments, the graft of the present invention includes acap and an elongate graft body extending from the cap, where the cap isconfigured to contact portions of the alimentary canal wall adjacent tothe primary opening, and the graft body is configured to extend into atleast a portion of the fistula tract. In other embodiments, the graft ofthe present invention includes a second cap configured to contactportions of the tissue adjacent to the secondary opening. In still otherembodiments, the graft of the present invention also includes anelongated tail, which may be used to eliminate the need for a separateseton placement step in the implantation procedure. The graft bodypreferably comprises a remodelable material, for example, a remodelableextracellular matrix material (ECM) such as submucosa. The inventionalso provides methods utilizing such a graft and medical products thatinclude such a graft enclosed within sterile packaging.

With reference now to FIG. 4, one embodiment of the biocompatible graft20 of the present invention includes a graft body 113 having a proximalend 114 and a distal end 115, a cap 22, and a tail 117. The graft bodymay have any suitable configuration. For example, the graft body mayhave a configuration that is generally convex, concave, S-shaped,straight, curved, flat, polygonal, conical, cylindrical, elliptical, orhemispherical, or it may have any other configuration capable of beinginserted into and secured within a fistula. In some embodiments, thegraft body is curved to conform to the shape of the fistula, therebyfacilitating introduction of the graft, a secure fit of the graft withinthe fistula, and less discomfort for the patient.

In the embodiments shown in FIGS. 3, 4, and 5, the graft body 113 has agenerally conical configuration that continuously tapers from a thickertrumpet-shaped proximal end 114 having a first diameter D1 to a thinfilamentous distal end 115 having a second diameter D2, where the firstdiameter D1 is greater than the second diameter D2. The degree of tapermay vary depending on a number of factors, including but not limited to,the diameter of each of the ends (D1 and D2) and the length L of thegraft. In other embodiments, the graft has a generally cylindrical bodyor a body in the form of a sheet, for example, as shown in FIGS. 6-8 and11. Although the sheet form material depicted in FIG. 11 is generally inthe shape of a rectangle, the graft body of the present invention, incertain aspects, can include sheet form material exhibiting any suitablerectilinear or curvilinear shape, for example, an isosceles triangle orany other suitable triangular or triangular-like shape, just to give afew non-limiting examples).

In some embodiments, a graft body is formed by folding or rolling, orotherwise overlaying one or more portions of a biocompatible material,such as a biocompatible sheet material, as described in U.S. ProvisionalApplication Ser. No. 60/763,521, titled “FISTULA GRAFTS AND RELATEDMETHODS AND SYSTEMS FOR TREATING FISTULAE” (Cook Biotech Incorporated),filed Jan. 31, 2006, which is hereby incorporated by reference in itsentirety. In certain embodiments, the overlaid biocompatible sheetmaterial can be compressed and dried or otherwise bonded into avolumetric shape such that a substantially unitary construct is formed.Such a substantially unitary graft body can then be placed in a fistulain a manner such that a cap contacts portions of the alimentary canalwall adjacent to the primary opening, and the graft body extends into atleast a portion of the fistula tract (and potentially fills the primaryfistula opening, the fistula tract, and/or any secondary fistulaopenings, or any portions thereof). The size of the cross section of thegraft body is generally constant along the length of the graft. In someembodiments, the graft body is configured so that its cross sectionincreases in size moving toward the cap. Such a configuration canprovide a more snug fit of the graft at or near the primary opening uponimplantation. In some embodiments, the graft body has portions that aretapered and/or curvilinear.

The graft body of the present invention may have any dimensions suitablefor implantation within a fistula. The graft body will be of sufficientsize and shape to extend into at least a portion of a fistula tract, andwill generally (but not necessarily) be of sufficient dimension to filla fistula, or a segment thereof; e.g., the primary fistula opening, afistula tract, and/or any secondary fistula openings, either alone or incombination with other similar or differing medical devices.

In certain embodiments having a tapered, generally conical shape, suchas the embodiments shown in FIGS. 3, 4, and 5, it is desirable for thegraft body to have a length L of about 1 to about 15 centimeters, afirst diameter D1 of about 1 to about 20 millimeters, and a seconddiameter D2 of about 0.1 to about 5 millimeters. More desirably, thegenerally conical graft body has a length L of about 3 to about 12centimeters, a first diameter D1 of about 2 to about 15 millimeters, anda second diameter D2 of about 0.5 to about 3.5 millimeters; and evenmore desirably, the graft body has a length L of about 5 to about 10centimeters, a first diameter D1 of about 5 to about 10 millimeters, anda second diameter D2 of about 1 to about 2 millimeters. The taper may ormay not be continuous along the length of the graft body.

As another example, in certain embodiments having a generallycylindrical graft body, such as the embodiments shown in FIGS. 6-8 and12-14, it is desirable for the graft body to have a length of at leastabout 0.2 centimeters, and in many situations at least about 1 to about20 centimeters. In illustrative embodiments, the graft body has a lengthof from about 2 to about 5 centimeters, or alternatively, from about 5to about 10 centimeters. Additionally, in certain embodiments, the graftbody will have a diameter, which may or may not be constant along thelength of the graft body, of from about 0.1 to about 25 millimeters, ormore typically from about 5 to about 10 millimeters. The graft of thepresent invention may be used to close any diameter of primary openingup to the limits of the diameter of the proximal end of the graft body.

In certain embodiments having a generally flat, sheet form graft body,such as the embodiment shown in FIG. 11, the size of the graft body fora particular treatment application will be based, at least in part, onthe general size and shape of the fistula being treated. A sheet formgraft body may be sized such that the diameter of the primary opening isless than the width of the sheet so that as the sheet is drawn into thefistula tract, it is forced to fold and/or roll over itself one or moretimes to conform to soft tissues surrounding the fistula, and isgradually “wedged” into the primary opening, and potentially at least aportion of the fistula tract and/or any secondary openings of thefistula, so as to block these spaces when sufficiently pulledtherethrough. Such lodging in place may be sufficient to obviate theneed for otherwise securing the graft to the soft tissues at or near theprimary opening, fistula tract, and/or any secondary openings.Nonetheless, in certain aspects, the graft is further secured to suchsoft tissues, for example, by suturing.

In certain embodiments of the present invention, the graft includes ananchoring adaptation to maintain the graft body within the fistula tractand/or to maintain the cap in place following implantation of the graft.For example, the graft may have protrusions on its outer surface, suchas the protrusions 18 shown in FIG. 3, to assist in anchoring the graftwithin the fistula. Other suitable anchoring adaptations include but arenot limited to barbs, hooks, sutures, adhesives, ribs, and the like.Such anchoring adaptations, while advantageous in certain embodiments ofthe invention, are not necessary to broader aspects of the invention.Illustratively, certain grafts are configured so that a cap is used tomaintain contact with portions of the alimentary canal wall adjacent tothe primary opening following implantation without the need for suchanchoring adaptations. Such a cap may assist in preventing the graftbody from being displaced or extruded from the fistula tract in a mannersimilar to a head on a nail, which prevents the elongated portion of thenail from being moved in a direction opposite the head. In otherembodiments of the invention, suitable anchoring adaptations may aid orfacilitate the maintenance of such contact.

The use of a cap on one or both ends of the graft body may to preventmigration or displacement of the graft body or extrusion of the graftbody from the fistula tract allows the use of a variety of differenttypes of graft bodies. The use of a tapered graft body having a proximalend that is adapted to be wedged into the fistula tract, although usedin some embodiments of the invention, is not necessary to properlysecure a graft within the fistula tract when the graft includes a cap onits proximal end. Although such a tapered design may still be used inconjunction with a cap, other simpler and less expensive graft bodiesmay be used instead of a tapered design, without sacrificing themechanical stability of the graft within the fistula tract.

The cap of the present invention may be of any suitable shape andconfiguration and may include any suitable device and/or material forcontacting portions of the alimentary canal wall adjacent to the primaryopening, and/or for contacting any secondary openings of the fistulatract. Illustratively, the cap can include one or more objects (e.g.,pieces of material or discrete shapes) that, together or alone, exhibita three-dimensional rectilinear or curvilinear shape. Suitablethree-dimensional rectilinear shapes can have any suitable number ofsides, and can include, for example, cubes, cuboids, tetrahedrons,prisms, pyramids, wedges, and variations thereof. Suitablethree-dimensional curvilinear bodies can include, for example, spheres,spheroids, ellipsoids, cylinders, cones, and any suitable variationsthereof (e.g., a segment of a sphere, or a truncated cone, etc.).Additional cap shapes and configurations can include, for example, adisc, a sphere, a hemisphere, a convex or concave form, a cone, a ring,a spring, a mesh, a lattice, a cylinder, an umbrella, a coil, a prong, apolygon, a flaring (trumpet-shaped) form, or any other suitable shape orform that extends laterally beyond the circumference of the graft body.Caps useful in the invention can be prepared, for example, as describedin U.S. Provisional Application Ser. No. 60/763,521, titled “FISTULAGRAFTS AND RELATED METHODS AND SYSTEMS FOR TREATING FISTULAE” (CookBiotech Incorporated), filed Jan. 31, 2006, which is hereby incorporatedby reference in its entirety.

Any cap present in an embodiment of the present invention (e.g., a capto be positioned at a rectal wall fistula opening and/or a cap to bepositioned at a vaginal wall fistula opening) may be constructed alongwith the elongate graft body to provide a single unitary construct, forexample, a single- or double-capped device formed from a single piece ofmaterial or other substance. In some embodiments, a particular cap maybe formed separately from an elongate graft body and then subsequentlycombined or otherwise retained in association with the graft body, forexample, by suturing the two together, applying an adhesive, usingmechanical fastener(s), or employing any other suitable means orcombination thereof. In one embodiment, the graft comprises an elongategraft body and two caps, wherein the caps are formed separately from thegraft body and are attached to opposite ends of the graft body, e.g.,before or during an implantation procedure.

In some forms, one or more caps are each formed separately from thegraft body, and then coupled to the graft body with an absorbable deviceor material. These coupling elements can exhibit any suitable size,shape, and configuration, and in some embodiments, take the form of anadhesive or one or more hooks, fasteners, barbs, straps, suture strands,or combinations thereof. Additionally, such devices and materials can beconfigured to degrade at varying rates upon being implanted in vivo. Inone embodiment, 2-0 vicryl suture material is used to join one or morecaps to an elongate graft body. Illustratively, a coupling element canbe adapted to desirably hold one or more caps in association with agraft body during product handling and implantation, and then uponimplantation, to degrade at a desirable rate. In some modes ofoperation, a cap and an elongate graft body, at least due in part todegradation of the coupling element, can uncouple or otherwise disengagefrom one another after a period of time following implantation, allowingthe cap to pass through and out of the body naturally. For caps to bepositioned on the rectal-side of a recto-vaginal fistula, for example,this decoupling can be facilitated and/or promoted by naturallyoccurring forces generated during peristalsis.

When formed separately, a cap may or may not be comprised of the samebiocompatible material(s) as the elongate graft body (or, if present,another cap). In certain aspects, the elongate graft body and/or any cappresent are comprised of a remodelable material, and in someembodiments, a remodelable collagenous material. Illustratively, a capand an elongate graft body can be formed from separate pieces ofremodelable, collagenous material (e.g., remodelable SIS material), andthereafter coupled to one another in accordance with the presentinvention. In one embodiment, a cap attached to one end of a graft bodycomprises a synthetic material (e.g., Nylon), while a cap attached tothe opposite end of the graft body comprises a naturally-derivedmaterial (e.g., an ECM material such as porcine SIS). In someembodiments, the use of a cap on one or both ends of the graft bodyserves to protect the graft body during remodeling, e.g. by protectingthe remodelable graft body from the fluids or other contents within themammalian body or from substances in the external environment near theprimary and/or secondary openings of the fistula.

The components of an inventive graft construct (e.g., a graft body,tail, and/or one or more caps), whether formed separately or together asa single unit, can be constructed in any suitable manner, for example,using any of the processes described herein. In some embodiments, agraft body, tail, and/or one or more caps are formed with areconstituted or otherwise reassembled ECM material. Graft bodies,tails, and/or caps can also be formed by folding or rolling, orotherwise overlaying one or more portions of a biocompatible material,such as a biocompatible sheet material. The overlaid biocompatible sheetmaterial can be compressed and dried or otherwise bonded into avolumetric shape such that a substantially unitary construct is formed.In some forms, an inventive graft component is constructed by randomlyor regularly packing one or more pieces of single or multilayer ECMsheet material within a mold and thereafter processing the packedmaterial. Elongate graft bodies useful in the invention can be prepared,for example, as described in U.S. Application Ser. No. 11/415,403,titled “VOLUMETRIC GRAFTS FOR TREATMENT OF FISTULAE AND RELATED METHODSAND SYSTEMS” (Cook Biotech Incorporated) filed May 1, 2006, which claimspriority to U.S. Provisional Application Ser. No. 60/676,118, filed Apr.29, 2005, which is incorporated by reference in its entirety.

When implanted in accordance with certain embodiments of the presentinvention, and contacting portions of the tissues adjacent to a primaryopening, the cap may or may not have a portion extending into theprimary opening. For example, in some aspects, the graft body isconfigured so that no portion of the cap resides within the primaryopening when the graft body is implanted, while in other aspects, thegraft is configured so that a portion of the cap does reside within theprimary opening when the graft is implanted. It is the graft as a whole,e.g., the combination of the cap and the graft body, that is configuredto block at least the primary opening of a fistula. However, neither thecap nor the graft body need be configured to block the primary fistulaopening independent of the other member, although either member may beso configured. Additionally, the cap, by itself, may or may not beconfigured to block the fistula tract. In this regard, blocking aparticular space or void can be accomplished by filling that space withthe cap, or a portion thereof. In certain aspects, the cap can beconfigured to fill the primary opening, the fistula tract (or anyportion thereof), and/or any secondary openings of the fistula. Suchfilling can, in some embodiments, seal off or substantially seal off theprimary opening, the fistula tract (or any portion thereof), and/or anysecondary openings of the fistula.

When suitably implanted, and thus extending into at least a portion ofthe fistula tract, the graft body may or may not have a portionextending into the primary opening. For example, in some aspects, thegraft is configured so that at least a portion of the graft body resideswithin the fistula tract but no portion of the graft body resides withinthe primary opening when the graft is implanted. In other aspects, thegraft body is configured to extend through the primary opening and intoat least a portion of the fistula tract when the graft body isimplanted. Again, it is the graft as a whole, e.g., the combination ofthe cap and the graft body, that is configured to block at least theprimary opening of a fistula. Additionally, the graft body, by itself,may or may not be configured to block the fistula tract. Further, thegraft body, by itself, may or may not be configured to block anysecondary fistula opening. In this regard, blocking a particular spaceor void can be accomplished by filling that space with the graft body,or a portion thereof. In certain embodiments, the graft body can beconfigured to fill the primary opening, the fistula tract (or anyportion thereof), and/or any secondary openings of the fistula. Suchfilling can, in some embodiments, seal off or substantially seal off theprimary opening, the fistula tract (or any portion thereof), and/or anysecondary openings of the fistula.

With reference now to FIG. 4, one embodiment of the cap is a flaring, ortrumpet-shaped cap 22, which projects laterally beyond the circumferenceof the proximal end 114 of the graft body 113. The cap 22 in thisembodiment is integral with the graft body 113.

With reference now to FIG. 5, another embodiment of the cap 22 is adisc-shaped structure that is attachable to the proximal end 114 of thegraft body 113. In certain embodiments, the transverse profile of thedisc may be oblong, convex, concave or any suitable combination thereof,for example. The means of affixing an attachable cap to a graft body maybe permanent or non-permanent. Where the device is affixed in anon-permanent manner, such as by absorbable sutures, the cap detachesfrom the graft body after a certain period of time, by which time thegraft body desirably has become ingrown into the fistula tract (e.g., asa result of the use of a graft material that supports the ingrowth ofhost tissue). The timing of the release of the cap may vary, dependingupon the thickness and dissolution characteristics of the material usedfor attaching the cap to the graft body. Desirably, the length of timeelapsed before the cap detaches is about 1 to about 8 weeks, moredesirably about 2 to about 6 weeks, and even more desirably about 4weeks.

The cap used in the graft of the present invention may have any suitabledimension. The suitable dimensions will depend upon several factors,including but not limited to, the size of the primary and/or secondaryopenings of the fistula tract and the size of the graft body. Desirably,the diameter (or other lateral dimension) of the cap is larger than thediameter (or width) of the graft body and larger than the diameter ofthe opening of the fistula tract that will be adjacent to the cap whenthe graft is implanted. As one example, the disc-shaped cap shown inFIGS. 5 and 6 desirably has a diameter of about 0.2 to about 5centimeters. More desirably, the diameter of the cap is about 0.5 toabout 2 centimeters, and even more desirably, the diameter is about 1centimeter. Desirably, the cap has a thickness of about 0.01 to about 1centimeter. More desirably, the cap has a thickness of about 0.05 toabout 0.5 centimeters, and even more desirably the thickness is about0.1 to about 0.3 centimeters.

The cap may be composed of any biocompatible absorbable ornon-absorbable material. The cap may be made of the same material as theremainder of the graft body. Examples of such materials are described indetail herein. Alternatively, the cap may be composed of a biocompatiblematerial that differs from the material of the remainder of the graftbody. In some embodiments, the cap is made of a hydrocarbon, plastic, orpolymer material. In other embodiments, the cap is made of a suitableabsorbable material such as an extracellular matrix material, whichallows the cap to become incorporated into the adjacent tissue, ratherthan becoming detached from the graft body.

In some embodiments of the present invention, the graft includes anelongated tail 117, as shown in FIGS. 4 and 5. Such a tail 117 may beattached to a probe and used to avoid the initial step of inserting aseton, thread or tie into the fistula tract before implanting a graft.Desirably, the tail 117 is about 5 to about 50 centimeters long. Moredesirably, the tail is about 10 to about 40 centimeters long. Even moredesirably, the tail is about 20 to about 30 centimeters long. Thediameter of the tail is desirably about 0.01 to about 1 millimeter, moredesirably about 0.1 to about 0.5 millimeters, and even more desirablyabout 0.2 to about 0.3 millimeters. The tail may be made of any suitablematerial, as described herein, and may or may not be made of the samematerial as the remainder of the graft.

The cap, graft body, and/or tail of the present invention may be formedas an integral unit (e.g., from a single piece of biocompatiblematerial), or alternatively, any component(s) of the graft may be formedseparately and then combined together, for example, using an adhesive,sutures, mechanical fastener(s), and/or any other suitable joiningmeans. When formed separately, the graft components may or may not becomprised of the same biocompatible material(s). In certain preferredaspects, the components are comprised of a remodelable material such asa remodelable extracellular matrix material. Illustratively, thecomponents can be formed from separate pieces of remodelable SISmaterial, and thereafter coupled to one another to form the graft.However, it should be noted that, in certain aspects, the components areformed from separate pieces of material, yet are retained in associationwith one another without the use of any other device or material (e.g.,sutures, an adhesive, etc.). For example, the cap(s) and the graft bodymay be held together by having at least one member (or any portionthereof) received around, through, over, etc., the other member (or anyportion thereof). The components of the present invention, whetherformed separately or together as a single unit, can be constructed inany suitable manner, for example, using any of the processes describedherein. In some embodiments, the components are formed with areconstituted or otherwise reassembled ECM material.

With reference now to FIG. 6, one embodiment of the graft of the presentinvention has a generally cylindrical graft body 23, which is secured ateach end of the fistula tract by means of a “button” shaped cap 22.These caps 22 may be affixed to the graft body by any suitable means,such as by absorbable sutures 121 passed through a plurality ofapertures 122 in the caps 22, in a manner similar to stitching a buttonto a shirt. Alternatively, the graft may incorporate an integral capthat extends laterally from one end of the graft body 23 and assists inpreventing dislodgement of the graft from the fistula tract. A secondcap or other means of securement may be used to secure the other end ofthe graft body and to assist in preventing dislodgement of the graft inthe opposite direction.

With reference now to FIG. 7, in one embodiment of the graft of thepresent invention, a cylindrical graft body 23 extends from a cap 22that is generally in the shape of a disk. The cap 22, which may be madeof an extracellular matrix material (e.g., SIS), may be configured tocontact portions of the alimentary canal wall adjacent to the primaryopening. The graft body 23, which may also be made of an extracellularmatrix material, is generally cylindrical and is configured to extendinto at least a portion of the fistula tract. The graft body 23 may ormay not be sized and shaped to fill the entire fistula tract.

With reference now to FIG. 8, an illustrative manner of using the graft20 of FIG. 7 to treat a patient is shown. As depicted, the graft 20 canbe implanted within a patient so that the cap 22 contacts portions ofthe alimentary canal wall 30 adjacent to the primary opening 31, and thegraft body 23 extends into at least a portion of the fistula tract 32.

With reference now to FIG. 9, shown is an alternative cap 22, which isgenerally in the shape of a bead. This illustrative cap can be coupledto or otherwise joined with any graft body described herein (e.g., thegraft body depicted in FIG. 11, as one non-limiting example). This capmay be comprised of an absorbable material, and generally sized andadapted to suitably contact portions of the tissues surrounding theprimary and/or secondary openings of a fistula tract.

FIG. 10A shows a side view of another alternative cap 22 of the presentinvention. FIG. 10B shows a cross sectional view of the cap of FIG. 10Aalong the line 10 b-10 b. The shape of this cap 22 generally resemblesthe shape of a lens or bowl. Such a cap may or may not have a hollowportion. This cap can be coupled to or otherwise joined with any graftbody described herein, and the cap and graft body can be joined in anysuitable manner and in any suitable configuration relative to oneanother, for example, so that peripheral regions of either the top orbottom face of the cap contacts portions of the alimentary canal walladjacent to the primary opening and/or portions of the tissues adjacentto the secondary opening.

With reference now to FIG. 11, shown is a perspective view of anotherillustrative graft body 23 of the present invention. This graft body 23comprises a compliant sheet form biocompatible material comprising twolayers of extracellular matrix material bonded together. This sheet formgraft body can be coupled to or otherwise joined with any of the capsdescribed herein, for example, the disk-shaped cap of FIG. 7 or thebead-shaped cap of FIG. 9, just to name a few. This sheet form graftbody can be prepared, for example, as described in U.S. Application Ser.No. 11/414,682, titled “FISTULA GRAFT WITH DEFORMABLE SHEET FORMMATERIAL” (Cook Incorporated), filed on Apr. 28, 2006, which claimspriority to U.S. Provisional Application Ser. No. 60/676,482, filed Apr.29, 2005, which are hereby incorporated by reference in their entirety.

The sheet form material is deformable upon impingement by soft tissuesurrounding a fistula (e.g., tissue surrounding the primary fistulaopening, the fistula tract, and/or any secondary fistula openings). Suchdeformable materials can include any of the extracellular matrix orother biocompatible materials described herein, for example, amultilaminate sheet of remodelable SIS material. Further, the sheet formgraft is sized and shaped so as to be deformable to a three-dimensionalvolumetric body extending into at least a portion of the fistula tract,and potentially filling at least a portion of the fistula tract, theprimary opening, and/or any secondary openings of the fistula. In sodoing, advantageous implant materials will also be sufficiently flaccidto avoid substantial cutting or tearing of the surrounding soft tissues.

In some embodiments of the present invention, the inventive grafts areuseful in treating recto-vaginal fistulas. Illustratively, such graftscan be configured to block at least a fistula opening occurring in arectal cavity wall, i.e., a rectal-side opening and potentially one ormore other segments of a recto-vaginal fistula, for example, a fistulatract and/or any openings occurring in a vaginal cavity wall. Inadvantageous embodiments, these products will at least include a cap andan elongate graft body extending from the cap, where the cap isconfigured to contact portions of the rectal cavity wall adjacent to thefistula opening, and the elongate graft body is configured to extendinto, and in some cases fill, at least a portion of a recto-vaginalfistula tract. Some of these products will additionally include a secondcap to be positioned in and/or around a vaginal wall fistula opening.While these products are particularly suited for treating recto-vaginalfistulae, it will be understood that such products may be useful intreating other types offistulae as well, and in some forms, are usefulin filling, blocking or otherwise treating non-fistula openings orpassages occurring in the body.

The grafts of the present invention and their components can exhibit anysuitable size and shape for treating recto-vaginal fistulae and otherbodily openings and passageways. A graft body may either have a constantor varying cross-sectional area along its length. Also, as discussed inmore detail below, some graft bodies of the invention can have one ormore lumens extending at least partially through the bodies along theirlength.

Referring now to FIG. 12, shown is a fistula plug 200 which is useful intreating recto-vaginal fistulae. Fistula plug 200 is comprised of anelongate plug body 201 having a first end 202 and a second end 203.Fistula plug 200 also includes a first cap 204 and a second cap 205,both of which are generally disk-shaped and have multiple aperturesformed therein. Plug body 201, which is generally in the shape of acylinder, is sized and adapted for placement in a fistula tract, and insome forms, is configured for filling at least a portion of a fistulatract. Plug body 201 can be formed with any suitable biocompatiblematerial, and in some embodiments, comprises a collagen-containingmaterial such as a remodelable ECM material. Plug body 201 has a centrallumen 206 extending through the construct along its length. Lumen 206,inter alfa, can enable plug body 201 to be deployed over an emplacedguidewire or other similar device. Additionally, there are multiple rowsof passages 207 occurring in plug body 201. These longitudinal rows arespaced evenly apart and staggered, and the passages 207 in each row areequidistant from one another along the length of plug body 201. Thelongitudinal axis of each passage runs through (and perpendicular to thelongitudinal axis of) central lumen 206 to allow communication betweenopposing sides of the exterior surface of plug body 201. Plug body 201also has multiple surface protuberances 208 extending out from itsexterior surface.

As depicted in FIG. 12, the first cap 204 and second cap 205 areinitially detached from elongate plug body 201, but are retained inassociation with plug body 201 by suture strand 209, which passesthrough plug body lumen 206, through and around the first cap 204, andthrough second cap 205. In this configuration, suture strand 209 can bemanipulated in such a fashion that the first cap 204 and second cap 205are brought in contact with first plug body end 202 and second plug bodyend 203, respectively. For example, the ends of suture strand 209 can bepulled tight, and portions of suture strand 209 can be secured together(e.g., knotted together) so that the two caps remain in contact with theends of plug body 201. Additionally or alternatively, the first cap 204and/or second cap 205 can be sutured or otherwise coupled or bonded toplug body 201. Depending on the particular application, bringing a capin contact with a plug body end (and potentially also securing the capto the plug body end) can occur before or during an implantationprocedure. For example, a first cap can be secured to a graft bodybefore the graft body is delivered to a fistula tract, while a secondcap can be secured to the graft body after delivery.

Passages formed or otherwise occurring in a graft body (such as thepassages 207 shown in FIG. 12) may be present in any suitable number andform. These passages can exhibit a variety of shapes and sizes, and canextend through all or a portion of the body. In some forms, one or morepassages extend from a graft body surface and include a generallycoherent passage wall. Illustratively, a tubular graft body having aninternal lumen extending through the body along its length can havepassages extending partially or entirely through a wall of the tube,e.g., from an exterior surface to an interior surface of the tube wall.Also, the spacing and size of a passage in a graft body relative toanother passage in the body, as well as the depth to which a particularpassage extends into a graft body, can vary. In some forms, the passagesare generally cylindrical voids, e.g., having diameters ranging fromabout 0.05 mm to about 15 mm, more typically from about 0.10 mm to about5 mm, and even more typically from about 0.1 mm to about 1.0 mm. Theseand other graft body passages useful in the present invention can bespaced any suitable distance from one another, and in some embodiments,are positioned in a particular pattern (e.g., in rows), although aplurality of passages can be randomly placed as well. Further, aplurality of passages in a construct can be configured so that any onepassage extends the same or a different distance into the constructrelative to any other passage in the construct.

In other embodiments of the present invention, the graft comprises anelongate graft body and an expandable cap. Such grafts can includemultiple expandable caps, and in some cases, include at least oneexpandable cap and at least one non-expandable cap. An expandable capuseful in the invention may comprise an expandable device including butnot limited to a resilient wire frame formed with a metallic orsynthetic polymeric material. In some aspects, an expandable capcomprises a material having the capacity to expand (e.g., a naturallyoccurring material such as a collagen-containing material or anon-naturally occurring material such as a syntheticpolymeric-containing material). Illustratively, an expandable capcomprises a sponge-form material containing an ECM material such aspericardium, submucosa or basement membrane.

With reference now to FIG. 13, shown is another embodiment of thefistula plug of the present invention. This plug is similar to thatshown in FIG. 12 except that second cap 205′ is expandable. In one modeof using such a plug, an appropriately-sized, dried plug body 201 isselected to suit the particular fistula being treated. The first cap 204and expandable second cap 205′ (which are loosely retained inassociation with plug body 201 by suture strand 209) may then beattached to first graft body end 202 and second graft body end 203,respectively, using suitable attachment means (e.g., an adhesive,sutures and/or the like). Next, the dried plug body 201 may be at leastpartially hydrated (optional) and then, in the case of a recto-vaginalfistula, for example, deployed by passing the second graft body end 203through the fistula opening on the rectal side and advancing it towardthe fistula opening on the vaginal side. This step may be facilitated byreceiving the fistula plug over an emplaced guidewire. The plug body 201is then advanced until the first cap 204 contacts portions of the rectalcavity wall adjacent to the fistula opening. Plug body 201 can beadvanced through the fistula tract in any suitable manner, and in someforms, is pulled through the tract by pulling on suture strand 209.Advantageously, plug body 201 will be sized and adapted so that uponbeing pulled into position (i.e., with the first cap 204 contacting therectal cavity wall), the expandable second cap 205′ will be located atthe fistula opening on the vaginal side and in a position to contactpatient tissue adjacent to (or otherwise in and/or around) thisvaginal-side opening upon expanding. The expandable second cap 205′ canmove between a first, compacted position and a second, expandedposition. When compacted, the second cap 205′ can be passed through thefistula tract. Once expanded, the second cap 205′ contacts patienttissue around the vaginal side opening and thus resists withdrawal backthrough the fistula tract. If present, the guidewire 210 can then beremoved, and suture strand 209 can be trimmed as necessary.

In some embodiments of the present invention, the fistula graft includesa cap, an elongate graft body extending from the cap, and an additionalcap that can be positioned at different locations along the graft bodyto provide adjustability to the overall graft. In use, this additionalcap may be effective, in certain aspects, to contact patient tissues inand around a fistula opening to block and/or fill the opening, and insome cases, to seal the opening. Such a cap may be translatable alongthe graft body, and in some embodiments, may be received over and slidalong the graft body so that the distance between the first cap and thesecond cap can be adjusted. Other adjustable devices useful in thepresent invention include, but are not limited to, a cap that can bepositioned along the graft body, yet does not slide over the graft body.Illustratively, such a cap or other suitable device can be clamped ontoor otherwise attached to the graft body from the side.

With reference now to FIG. 14, shown is a perspective view of a fistulagraft 300 of the present invention which can be used to treat fistulassuch as recto-vaginal fistulas, for example. Fistula graft 300 includesa biocompatible graft body 303 that is configured to block at least asegment of a fistula, e.g., a fistula tract and/or one or more fistulaopenings such as a primary opening or secondary opening. The graft 300includes a first cap 302, a graft body 303 that extends from the cap302, and a distal end 304. The first cap 302, which may be formed from asynthetic material (such as Nylon), may generally take any suitable form(such as the form of a disk) and configured to contact portions oftissue adjacent to a fistula opening. One side of the cap 302 mayinclude a generally disk-shaped cavity (having a diameter smaller thanthat of the first cap 302) in which a disk-shaped gasket 305 resides, asshown in FIGS. 14 and 16. Gasket 305 may be formed from a tissueingrowth material, and may be attached to the cap 302 with absorbablesutures 306, although the two may be attached or otherwise held togetherin any suitable manner. The graft body 303, which may be formed from anECM material, may generally take the shape of a cylinder and beconfigured to extend into at least a portion of a fistula tract.

The graft 300 may also include a second cap 307 which may be receivedover the distal end 304 and configured to slide along the graft body303. In some embodiments, the second cap is formed with a vacuum pressedECM material such as SIS. To create such an opening through which thegraft body 303 can be received, portions of the second cap 307 may becut (and in some cases removed). In the embodiment shown in FIGS. 14 and15, an X-shaped cut in the second cap 307 provides flaps 308. In otherembodiments, cuts of other shapes may be made to provide an openingthrough which a fistula plug can be received, including but not limitedto, a circular cut or an S-shaped cut. Flaps 308 may be useful insecuring second cap 307 to graft body 303, e.g., by adhering or suturingthe flap(s) 308 to the graft body 303.

In one mode of operation, graft body 303 is deployed by passing thedistal end 304 of the graft body 303 (with the second cap 307 removedfrom the graft body) through a first fistula opening (e.g., an openingin a rectal cavity wall) and advancing it through the fistula tract andtoward a second fistula opening (e.g., an opening in a vaginal cavitywall). This step may be facilitated by receiving the graft over anemplaced guidewire (in which case graft body 303 would need to beadapted to be able to receive such a device), The graft body 303 maythen be advanced until the first cap 302 and gasket 305 contact portionsof the tissues adjacent to the first fistula opening. By maintainingthis contact for a sufficient period of time, new tissue can grow intothe gasket 305, which can promote and/or facilitate blockage of thefistula opening, and in some cases, sealing off of the opening. Thegraft body 303 can be advanced through the fistula tract in any suitablemanner, and in some embodiments, is pulled through the tract by pullingon a suture strand which is connected to or otherwise associated with(e.g., threaded through) the graft body 303. In other embodiments, agrasping device such as surgical hemostasis is used to pull the graftinto position. In general, the graft body 303 will be sized so that uponbeing pulled or pushed into position (i.e., with the first cap 302 andgasket 305 contacting portions of the tissues adjacent to the firstfistula opening), the distal end 304 of the graft body 303 will extendbeyond the second fistula opening. The second cap 307 can then bereceived over the graft body distal end 304 and advanced until itcontacts portions of the tissue wall adjacent the second fistulaopening. The second cap 307 is then attached to the graft body 303,e.g., by suturing flaps 308 to the graft body, and any excess portion ofdistal end 304 can be removed (e.g., trimmed) as desired. If a guidewireis present, it can then be removed. In some embodiments, the graft 300is similarly deployed except that the distal end 304 of the graft body303 is first passed through a fistula opening occurring in a vaginalcavity wall so that it extends beyond an opening occurring in a rectalcavity wall.

The first cap 302 and gasket 305 may or may not include one or more ofthe same materials. In one embodiment, the gasket 305 is formed with atissue ingrowth material, and the first cap 302 is formed with amaterial having relatively less receptivity to tissue ingrowth, and insome embodiments, with a material having very little or no receptivityto tissue ingrowth. Illustratively, the first cap 302 can be formed witha rigid or semi-rigid synthetic polymeric material, and the gasket 305can be formed with a pliable remodelable collagenous material.

Seal enhancement devices such as gasket 305 come in a variety of shapesand sizes, and can be configured in variety of manners in and around acap to promote and/or facilitate sealing off of a fistula opening. Inaddition to gasket 305, the present invention provides other devices andmaterials which can be incorporated into or otherwise associated with acap to provide an enhanced seal between the cap and the tissues adjacentto the fistula opening. In some embodiments, such devices comprise aflowable or sheet-form tissue ingrowth material residing in and/or on acap.

With reference now to FIG. 17, shown is a top view of an illustrativemedical product 100 of the present invention that includes a graft 20sealed within sterile medical packaging. In particular, medical product100 has packaging including a backing layer 101 and a front film layer102 (shown partially drawn away from the backing layer 101). The graft20 is sealed between the backing layer 101 and the film 102 by aboundary of pressure-adhesive 103, which may be of any suitable shapeand size. A cut-out 104 may be provided in the backing layer 101 toassist a user in separating the film layer 102 from the backing layer101.

Sterilization of the medical product 100 may be achieved, for example,by irradiation, ethylene oxide gas, or any other suitable sterilizationtechnique, and the materials and other properties of the medicalpackaging can be selected accordingly. Also, grafts of the invention canbe contained in sterile packaging in any suitable state. Suitable statesinclude, for example, a hydrated or dehydrated state. The grafts can bedehydrated by any means known in the art (e.g., lyophilization or airdried). If a graft of the present invention is stored in a dehydratedstate, it is preferred that it retains all of its biological andmechanical properties (e.g., shape, density, flexibility, etc.) uponrehydration.

The materials and other properties of the packaging can be selectedaccording to the needs and desires of the end user of the productcontained therein. For example, the package can include indicia tocommunicate the contents of the package to a person and/or a machine,computer, or other electronic device. Such indicia may include thedimensions of, the type of materials used to form, and/or the physicalstate of, the contents of the package. In certain embodiments, a graftis packaged for sale with instructions for use. For example, inparticularly preferred embodiments, a medical product includes at leastone graft (including a graft body, one or more caps, and/or a tail, asdistinct components or as an integral unit) sealed within a sterilepackage, wherein the packaging has visible indicia identifying the graftand/or the graft components as having certain physical characteristics.The packaging may contain or otherwise be associated with printedmaterials identifying the contents as having such physicalcharacteristics and including information concerning its use as a graftfor treating fistulas. The packaging may also include visible indiciarelating to the dimensions of the graft, and/or relating to thetreatment site(s) for which the graft is configured.

The present invention also provides a line of medical products thatinclude one or more grafts or graft components, such as those describedherein, enclosed within a sealed package. When the medical productincludes a plurality of grafts or graft components, the products caneach be of substantially the same size and shape, or, alternatively, canvary with respect to size and shape.

Turning now to a discussion of the materials that may be used to formthe graft of the present invention, the graft may be made of anybiocompatible material suitable for implantation into a mammalian body.Desirably, the graft is made of a single, non-allergenic biological orsynthetic material. More desirably, the graft is made of a remodelablematerial.

Suitable biological materials may be rendered non-cellular duringprocessing to avoid immunological rejection. Such biological tissues maybe implanted in potentially infected surgical fields and resistinfection, unlike some synthetic preparations that may elicit a foreignbody reaction or act as a nidus for infection. Suitable biologicalmaterials that may be used in the present invention include, but are notlimited to, heterograft material (i.e., cross-species material, such astissue material from a non-human donor to a human recipient), allograftmaterial (i.e., tissue material from a human cadaveric donor), and/orautograft material (i.e., where the donor and the recipient are the sameindividual). Desirably, the material promotes angiogenesis and/orsite-specific tissue remodeling. Further, any exogenous bioactivesubstances incorporated into an ECM material may be from the samespecies of animal from which the ECM material was derived (e.g.autologous or allogenic relative to the ECM material) or may be from adifferent species from the ECM material source (xenogenic relative tothe ECM material). In certain embodiments, ECM material will bexenogenic relative to the patient receiving the graft, and any addedexogenous material(s) will be from the same species (e.g. autologous orallogenic) as the patient receiving the graft. Illustratively, humanpatients may be treated with xenogenic ECM materials (e.g. porcine-,bovine- or ovine-derived) that have been modified with exogenous humanmaterial(s) as described herein, those exogenous materials beingnaturally derived and/or recombinantly produced.

Autograft tissue is grown from a skin biopsy of the patient. Once thefibroblasts have regenerated and formed enough new tissue, the newtissue may be injected back into the surgical site of the same patient.This process takes several weeks to complete, but avoids tissuerejection and disease transmission. One such product is Isolagen(Isolagen Inc.—Houston, Tex.).

Suitable cadaveric materials include, but are not limited to, cadavericfascia and cadaveric dura matar. Specific suitable cadaveric allograftsinclude, but are not limited to, AlloDerm, (LifeCell Corp.—Branchburg,N.J.), Cymetra, (LifeCell Corp.—Branchburg, N.J.), Dermaloga, Fascion(Fascia Biosystems, LLC—Beverly Hills, Calif.), and Suspend(Mentor—Irving, Tex.). These products are freeze-dried, or lyophilized,acellular dermal tissue from cadaveric donors. Some requirereconstitution before implantation. Although disease transmission orantigenic reaction is possible, the risk may be minimized by anextensive screening and processing of the material.

Heterograft materials are taken from a donor of one species and graftedinto a recipient of another species. Examples of such materials include,but are not limited to, Surgisis (Cook Surgical—Bloomington, Ind.),Permacol (TSL—Covington, Ga.), Pelvicol (Bard Inc.—Murray Hill, N.J.)and Peri-Guard, (Bio-Vascular Inc.—St Paul, Minn.). In one embodiment ofthe present invention, an injectable heterograft, such as a heterograftof small intestinal submucosa or other material having a viscositysufficient to prevent the material from running out or being squeezedout of the fistula, is used.

The materials used to form the grafts of the present invention shouldgenerally be biocompatible, and in desirable embodiments, are comprisedof a remodelable material. Desirably, the material has a collagenoustissue frame that remains intact to allow for ingrowth of host cells andeventual reconstruction of the host tissue itself. Desirable remodelablecollagenous materials can be provided, for example, by collagenousmaterials isolated from a warm-blooded vertebrate, and especially amammal. Such isolated collagenous material can be processed so as tohave remodelable, angiogenic properties and promote cellular invasionand ingrowth. Remodelable materials may be used in this context topromote cellular growth on, around, and/or within tissue in which agraft of the invention is implanted, e.g., around tissue defining afistula tract or an opening to a fistula.

Suitable remodelable materials can be provided by collagenousextracellular matrix (ECM) materials possessing biotropic properties.For example, suitable collagenous materials include ECM materials suchas submucosa, renal capsule membrane, dermal collagen, dura mater,pericardium, serosa, peritoneum or basement membrane layers, includingliver basement membrane. Suitable submucosa materials for these purposesinclude, for instance, intestinal submucosa including small intestinalsubmucosa, stomach submucosa, urinary bladder submucosa, and uterinesubmucosa. Submucosa useful in the present invention can be obtained byharvesting such tissue sources and delaminating the submucosa fromsmooth muscle layers, mucosal layers, and/or other layers occurring inthe tissue source. For additional information as to submucosa useful inthe present invention, and its isolation and treatment, reference can bemade, for example, to U.S. Pat. Nos. 4,902,508, 5,554,389, 5,993,844,6,206,931, and 6,099,567.

Submucosa or other ECM tissue used in the invention is preferably highlypurified, for example, as described in U.S. Pat. No. 6,206,931 to Cooket al. Thus, preferred ECM material will exhibit an endotoxin level ofless than about 12 endotoxin units (EU) per gram, more preferably lessthan about 5 EU per gram, and most preferably less than about 1 EU pergram. As additional preferences, the submucosa or other ECM material mayhave a bioburden of less than about 1 colony forming units (CFU) pergram, more preferably less than about 0.5 CFU per gram. Fungus levelsare desirably similarly low, for example less than about 1 CFU per gram,more preferably less than about 0.5 CFU per gram. Nucleic acid levelsare preferably less than about 5 μg/mg, more preferably less than about2 μg/mg, and virus levels are preferably less than about 50 plaqueforming units (PFU) per gram, more preferably less than about 5 PFU pergram. These and additional properties of submucosa or other ECM tissuetaught in U.S. Pat. No. 6,206,931 may be characteristic of any ECMtissue used in the present invention.

A typical layer thickness for an as-isolated submucosa or other ECMtissue layer that may be used in the invention ranges from about 50 toabout 250 microns when fully hydrated, and more typically from about 50to about 200 microns when fully hydrated, although isolated layershaving other thicknesses may also be obtained and used. These layerthicknesses may vary with the type and age of the animal used as thetissue source. These layer thicknesses may also vary with the source ofthe tissue obtained from the animal source.

In some embodiments of the present invention, one or more bioactiveagents are included. As used herein, the phrase “bioactive agent” refersto any pharmaceutically active agent that produces an intendedtherapeutic effect on the body to treat or prevent conditions ordiseases. Such bioactive agents may be incorporated into the graftmaterial(s), coated onto the graft material(s), or included in the graft(or portions thereof) in any other suitable manner. For example, abioactive agent (or a bioactive agent combined with anotherbiocompatible material) may be coated on a graft body or contained inpassages formed in a graft body, and be configured to release over acertain period of time.

Suitable bioactive agents may include one or more bioactive agentsnative to the source of the ECM tissue material. For example, asubmucosa or other remodelable ECM tissue material may retain one ormore growth factors including but not limited to basic fibroblast growthfactor (FGF-2), transforming growth factor beta (TGF-beta), epidermalgrowth factor (EGF), cartilage derived growth factor (CDGF), and/orplatelet derived growth factor (PDGF). In addition, submucosa or otherECM materials when used in the invention may retain other nativebioactive agents including but not limited to proteins, glycoproteins,proteoglycans, and glycosaminoglycans. For example, ECM materials mayinclude heparin, heparin sulfate, hyaluronic acid, fibronectin,cytokines, and the like. Thus, generally speaking, a submucosa or otherECM material may retain one or more bioactive components that induce,directly or indirectly, a cellular response such as a change in cellmorphology, proliferation, growth, protein or gene expression.

In addition or as an alternative to the inclusion of such nativebioactive components, non-native bioactive components such as thosesynthetically produced by recombinant technology or other methods (e.g.,genetic material such as DNA), may be incorporated into an ECM material.These non-native bioactive components may be naturally-derived orrecombinantly produced proteins that correspond to those nativelyoccurring in an ECM tissue, but perhaps of a different species. Thesenon-native bioactive components may also be drug substances.Illustrative drug substances that may be added to material layersinclude, for example, anti-clotting agents, e.g. heparin, antibiotics,anti-inflammatory agents, and anti-proliferative agents, e.g. taxolderivatives such as paclitaxel. Such non-native bioactive components canbe incorporated into and/or onto ECM material in any suitable manner,such as by surface treatment (e.g., spraying) and/or impregnation (e.g.,soaking), just to name a few non-limiting examples.

Other suitable bioactive agents that may be used in the presentinvention include, but are not limited to: antithrombotics, includingbut are not limited to anticoagulants (such as thrombin, Factor Xa,Factor VIIa, tissue factor inhibitors, heparin, low molecular weightheparin, covalent heparin, synthetic heparin salts, coumadin,bivalirudin (hirulog), hirudin, argatroban, ximelagatran, dabigatran,dabigatran etexilate, D-phenalanyl-L-poly-L-arginyl, chloromethy ketone,dalteparin, enoxaparin, nadroparin, danaparoid, vapiprost, dextran,dipyridamole, omega-3 fatty acids, vitronectin receptor antagonists,DX-9065a, CI-1083, JTV-803, razaxaban, BAY 59-7939, and LY-51,7717),antiplatelets (such as glycoprotein thromboxane A2, ADP-inducedglycoprotein IIb/IIIa, phosphodiesterase inhibitors, eftibatide,tirofiban, orbofiban, lotrafiban, abciximab, aspirin, ticlopidine,clopidogrel, cilostazol, dipyradimole, nitric oxide sources such assodium nitroprussiate, nitroglycerin, S-nitroso and N-nitrosocompounds), and fibrinolytics (such as plasminogen activators, thrombinactivatable fibrinolysis inhibitor (TAFI) inhibitors, other enzymeswhich cleave fibrin, alfimeprase, alteplase, anistreplase, reteplase,lanoteplase, monteplase, tenecteplase, urokinase, streptokinase, orphospholipid encapsulated microbubbles; and other bioactive materialssuch as endothelial progenitor cells or endothelial cells).

Still other non-limiting examples of suitable bioactive agents that maybe used in the present invention include, but are not limited to:antiproliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas (GP) II/III_(a) inhibitors and vitronectin receptor antagonists;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);anti-inflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetaminophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), tacrolimus, everolimus, azathioprine,mycophenolate mofetil); angiogenic agents: vascular endothelial growthfactor (VEGF), fibroblast growth factor (FGF); angiotensin receptorblockers; nitric oxide and nitric oxide donors; anti-senseoligionucleotides and combinations thereof; cell cycle inhibitors, mTORinhibitors, and growth factor receptor signal transduction kinaseinhibitors; retenoids; cyclin/CDK inhibitors; endothelial progenitorcells (EPC); angiopeptin; pimecrolimus; angiopeptin; HMG co-enzymereductase inhibitors (statins); metalloproteinase inhibitors(batimastat); protease inhibitors; antibodies, such as EPC cell markertargets, CD34, CD133, and AC 133/CD133; Liposomal Biphosphate Compounds(BPs), Chlodronate, Alendronate, Oxygen Free Radical scavengers such asTempamine and PEA/NO preserver compounds, and an inhibitor of matrixmetalloproteinases, MMPI, such as Batimastat.

ECM materials used in the present invention may be free of additional,non-native crosslinking, or may contain additional crosslinking. Suchadditional crosslinking may be achieved by photo-crosslinkingtechniques, by chemical crosslinkers, or by protein crosslinking inducedby dehydration or other means. However, because certain crosslinkingtechniques, certain crosslinking agents, and/or certain degrees ofcrosslinking can destroy the remodelable properties of a remodelablematerial, where preservation of remodelable properties is desired, anycrosslinking of the remodelable ECM material can be performed to anextent or in a fashion that allows the material to retain at least aportion of its remodelable properties. Chemical crosslinkers that may beused include for example aldehydes such as glutaraldehydes, diimidessuch as carbodiimides, e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ribose orother sugars, acyl-azide, sulfo-N-hydroxysuccinamide, or polyepoxidecompounds, including for example polyglycidyl ethers such asethyleneglycol diglycidyl ether, available under the trade name DENACOLEX810 from Nagese Chemical Co., Osaka, Japan, and glycerol polyglycerolether available under the trade name DENACOL EX 313 also from NageseChemical Co. Typically, when used, polyglycerol ethers or otherpolyepoxide compounds will have from about 2 to about 10 epoxide groupsper molecule.

In certain embodiments, the present invention provides grafts includinga multilaminate material. Such multilaminate materials can include aplurality of ECM material layers bonded together, a plurality of non-ECMmaterials bonded together, or a combination of one or more ECM materiallayers and one or more non-ECM material layers bonded together. To forma multilaminate ECM material, for example, two or more ECM segments arestacked, or one ECM segment is folded over itself at least one time, andthen the layers are fused or bonded together using a bonding technique,such as chemical cross-linking or vacuum pressing during dehydratingconditions. An adhesive, glue or other bonding agent may also be used inachieving a bond between material layers. Suitable bonding agents mayinclude, for example, collagen gels or pastes, gelatin, or other agentsincluding reactive monomers or polymers, for example cyanoacrylateadhesives. In addition, bonding can be achieved or facilitated betweenECM material layers using chemical cross-linking agents such as thosedescribed above. A combination of one or more of these withdehydration-induced bonding may also be used to bond ECM material layersto one another.

A variety of dehydration-induced bonding methods can be used to fusetogether portions of an ECM material. In one preferred embodiment,multiple layers of ECM material are compressed under dehydratingconditions. In this context, the term “dehydrating conditions” isdefined to include any mechanical or environmental condition whichpromotes or induces the removal of water from the ECM material. Topromote dehydration of the compressed ECM material, at least one of thetwo surfaces compressing the matrix structure can be water permeable.Dehydration of the ECM material can optionally be further enhanced byapplying blotting material, heating the matrix structure or blowing air,or other inert gas, across the exterior of the compressed surfaces. Oneparticularly useful method of dehydration bonding ECM materials islyophilization.

Another method of dehydration bonding comprises pulling a vacuum on theassembly while simultaneously pressing the assembly together. Again,this method is known as vacuum pressing. During vacuum pressing,dehydration of the ECM materials in forced contact with one anothereffectively bonds the materials to one another, even in the absence ofother agents for achieving a bond, although such agents can be usedwhile also taking advantage at least in part of the dehydration-inducedbonding. With sufficient compression and dehydration, the ECM materialscan be caused to form a generally unitary ECM structure.

It is advantageous in some aspects of the invention to perform dryingand other operations under relatively mild temperature exposureconditions that minimize deleterious effects upon any ECM materialsbeing used, for example native collagen structures and potentiallybioactive substances present. Thus, drying operations conducted with noor substantially no duration of exposure to temperatures above humanbody temperature or slightly higher (e.g., no higher than about 38° C.)will preferably be used in some forms of the present invention. Theseinclude, for example, vacuum pressing operations at less than about 38°C., forced air drying at less than about 38° C., or either of theseprocesses with no active heating—at about room temperature (i.e., about25° C.) or with cooling. Relatively low temperature conditions also, ofcourse, include lyophilization conditions.

Grafts of the present invention may include biocompatible materialsderived from a number of biological polymers, which can be naturallyoccurring or the product of in vitro fermentation, recombinant geneticengineering, and the like. Purified biological polymers can beappropriately formed into a substrate by techniques such as weaving,knitting, casting, molding, and extrusion. Suitable biological polymersinclude, without limitation, collagen, elastin, keratin, gelatin,polyamino acids, polysaccharides (e.g., cellulose and starch) andcopolymers thereof.

Suitable biocompatible grafts of the invention can also include avariety of synthetic polymeric materials including but not limited tobioresorbable and/or non-bioresorbable plastics. Bioresorbable, orbioabsorbable polymers that may be used include, but are not limited to,poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polygalactin,hyaluronic acid, polydioxanone, polyorthoester, polyanhydride,poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyhydroxyalkanaates,polyphosphoester, polyphosphoester urethane, poly(amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates, andpolyphosphazenes. These or other bioresorbable materials may be used,for example, where only a temporary blocking or closure function isdesired, and/or in combination with non-bioresorbable materials whereonly a temporary participation by the bioresorable material is desired.

Non-bioresorbable, or biostable polymers that may be used include, butare not limited to, polytetrafluoroethylene (PTFE) (including expandedPTFE), polyethylene terephthalate (PET), polyurethanes, silicones, andpolyesters and other polymers such as, but not limited to, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymersand copolymers, vinyl halide polymers and copolymers, such as polyvinylchloride; polyvinyl ethers, such as polyvinyl methyl ether;polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers;polyamides, such as Nylon 66 and polycaprolactam; alkyd resins,polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins,polyurethanes; rayon; and rayon-triacetate.

Desirably, the biological or synthetic material used in the presentinvention assists in reconstruction of the host tissues, elicits littleimmunological reaction, and has some inherent resistance to infection.Such material may desirably allows incorporation of the graft into thehost tissue of the fistula (rather than complete absorption of the graftinto the surrounding tissue), thereby occluding the fistula.

In one embodiment of the present invention, a drug, such as anantibiotic, is incorporated into the graft, as an extra precaution ormeans of treating any residual infection within the fistula. The graftmay also be used in conjunction with a sealant or sclerosing solutionwhich may be injected into the main fistula tract and any side branches.Several possible sealants are described in the prior art. One of themore commonly used sealants is fibrin glue, known as Tisseal (BaxterInc.). The glue is prepared by mixing coagulation activation factorswith fibrinogen, which react to form fibrin. The fibrin forms a matrix,which acts as a scaffold for tissue ingrowth and results in the sealingof the fistula tract.

Turning now to a general discussion regarding methods for treatingfistulas according to the present invention, suitable treatment methodsinclude providing a graft, such as any of those described herein, andimplanting the graft within a patient so that: (i) the graft blocks atleast the primary opening of a fistula, i.e., the primary opening andpotentially one or more other segments of a fistula, for example, thefistula tract and/or any secondary openings; (ii) the cap contactsportions of the tissues adjacent to the primary opening and/or portionsof the tissues surrounding any secondary openings; and (iii) the graftbody extends into at least a portion of the fistula tract. The graftsand methods of the present invention can be used to treat any fistula,such as a fistula having a primary opening in a wall of an alimentarycanal. In some aspects, the invention provides grafts and methods usefulfor blocking openings anywhere on or within the body of a patient, forexample, blocking at least the primary opening of a urethro-vaginalfistulas, vesico-vaginal fistulas, tracheo-esophageal fistulas,gastro-cutaneous fistulas, fistulas occurring between the vascular andgastrointestinal systems, and any number of anorectal fistulas, such asrecto-vaginal fistula, recto-vesical fistulas, recto-urethral fistulas,or recto-prostatic fistulas. Also, inventive products and methods can beused to treat a fistula regardless of its size and shape, and in someforms, are used to treat fistulas having a primary opening, secondaryopening(s), and/or fistula tract with a diameter ranging from about 1 toabout 20 millimeters, more typically from about 5 to about 10millimeters.

Grafts of the invention can be implanted using any suitable deliverymethod or placement technique. Illustratively, a graft body can beimplanted by pulling or pushing the graft body into a suitable positionwithin a fistula. In some embodiments of the present invention, thegraft includes a tail in association with the graft body, for example,sutured, glued, tied, or attached by another suitable means to the graftbody. This tail can be used to pull the graft body into a suitableposition within a fistula. For example, the distal end of the graft bodyor the tail of the graft can be pulled through the primary opening ofthe fistula and towards the secondary opening until the cap contactsportions of the alimentary canal wall adjacent to the primary openingand/or the proximal end of the graft body becomes wedged into theprimary opening, as described above. In certain embodiments, suchimplantation can be accomplished using a fistula probe or scope oranother suitable instrument, for example, an appropriately configuredpair of surgical hemostats that includes a portion passable into asecondary opening, through the fistula tract, and potentially out of theprimary opening. Thereafter, the graft body can be releasably grasped bythe probe or otherwise coupled to the probe and pulled into the primaryopening. The graft body may also be secured at one or both ends by meansof sutures, cap(s), or any other suitable method of affixation.

In some embodiments of the present invention, the tail of the graft isused to sufficiently locate a suitable fistula graft within a patient,and then is removed from the graft, for example, using cutting shears.In alternative embodiments, the tail is made from a remodelable orotherwise absorbable material such that it can be left in place withinthe fistula tract. In these forms, the absorbable tail can be used toanchor or otherwise suitably secure the fistula graft within theimplantation site. For example, the tail can be tied to the tissues ofthe patient at a suitable location, for example, a location just insideor external to a secondary fistula opening. Further, in alternativeembodiments, an illustrative fistula graft can be positioned so that itspans the entire length of a fistula tract, i.e., from the primaryopening to a location at or external to a secondary opening. In theseembodiments, string or suture, for example, can be used to secure thetail of the graft to the tissue of the patient at an external location.

In some embodiments of the method of the present invention, afterimplanting a graft into a fistula tract, either end of the graft or bothends of the graft are secured by sutures to ensure that the graft is notdisplaced and/or expelled through the primary opening or the secondaryopening. The suture may be formed as an integral part of the graft or asa separate component. Where the graft includes a cap on the proximal endof the graft body, it may be desirable to secure the distal end of thegraft at the level of the secondary opening for additional assurancethat the graft will not be displaced or expelled through the primaryopening. The means of securing the distal end of the graft may besimilar to those used to secure the proximal end of the graft or may beany other suitable means of securement. The use of a cap on each end ofthe graft may be desirable to avoid the need for using sutures andpiercing the tissues of the patient to firmly secure the graft withinthe fistula tract.

Fistula treatment methods of the invention may include an endoscopicvisualization (fistuloscopy) step, as disclosed in co-pendingapplication Ser. No. 10/945,634 (Armstrong), hereby incorporated byreference in its entirety. Such endoscopic visualization can be used,for example, to determine the shape and size of the fistula, which inturn can be used to select an appropriately sized and shaped graft fortreating the fistula. Illustratively, a very thin flexible endoscope canbe inserted into a secondary opening of the fistula and advanced underdirect vision through the fistula tract and out through the primaryopening. By performing fistuloscopy of the fistula, the primary openingcan be accurately identified. Also, cleaning of the fistula can beperformed prior to and/or during deployment of a graft of the invention.For example, an irrigating fluid can be used to remove any inflammatoryor necrotic tissue located within the fistula prior to engrafting theproduct. In certain embodiments, one or more antibiotics are applied tothe graft and/or the soft tissues surrounding the fistula as an extraprecaution or means of treating any residual infection within thefistula.

In some embodiments of the method of the present invention, a fistula isdrained prior to receiving a graft of the invention therein. Suchdraining can be accomplished by inserting a narrow diameter rubber drainknown as a seton through the fistula. The seton is passed through thefistula tract and tied as a loop around the contained tissue and leftfor several weeks or months. This procedure is usually performed todrain infection from the area, and to mature the fistula tract prior toa definitive closure procedure.

The grafts of the present invention can be modified before, during,and/or after deployment. Illustratively, the graft may be cut, trimmed,sterilized, and/or treated (e.g., brought into contact, impregnated,coated, etc.) with one or more desirable compositions, such as any ofthose disclosed herein, e.g., anticoagulants (e.g., heparin), growthfactors or other desirable property modifiers. In certain aspects,following deployment of a graft in accordance with the presentinvention, one or more portions of the graft, for example, materialprotruding from the primary opening and/or any secondary opening, aretrimmed off or otherwise removed.

In other embodiments, the graft is anchored within the fistula bythreading a securing device having a central lumen, over the tail of thegraft and securing it into position at skin level (e.g., by crimpingit). In yet another embodiment, further anchoring of the graft isachieved by using a material such as a small intestinal submucosaheterograft (a freeze-dried material that requires rehydration beforeuse) for the graft and inserting the graft into the tract before thegraft material has been fully expanded by hydration. Any other suitablemeans of securement, such as introducing adhesive into the fistulatract, may also be used to anchor the graft within the fistula.

In one embodiment, autologous fibrin glue is used in conjunction withthe fistula graft to supplement the adhesive and occlusive properties ofthe disclosed invention (e.g., Symphony PCS, DePuy AcroMed Inc.). Thisinvolves the use of an autologous composite of platelets and growthfactors derived from the patient's own blood. The composite may bederived from a fresh sample of blood drawn from the patient at the timeof surgery. The blood may then be centrifuged, and the platelets, whichcontain growth factors such as epidermal growth factor (EGF) andtransforming growth factor-beta (TGFβ), harvested. Having centrifugedthe blood, retrieved the platelet “pellet” and prepared the composite,the sealant may then be injected into the fistula tract(s) to helpmaintain the graft in place.

Closure of a fistula tract may be performed as a one-stage or two-stageprocedure. As a one-stage procedure, the fistula tract is closed orsealed at the same time as the initial surgery. The primary advantage ofthis method is that it avoids a second operation and minimizes expenseand inconvenience. However, immediate implantation of the graft into anunprepared and possibly infected fistula tract may result in a secondaryinfection. As a two-stage procedure, a seton is first placed through thefistula tract to allow mechanical drainage of the fistula tract. Severalweeks later, the seton is removed and the graft is inserted into thefistula. In certain embodiments of the method of the present invention,a tail associated with the graft body is used to eliminate the setonplacement step.

Turning now to particular methods of the invention for deliveringfistula plugs such as that shown in FIG. 12 to a fistula tract, such asa recto-vaginal fistula, in one mode of operation, preparing aninventive plug for use includes selecting an appropriately-sized, driedplug body 201 for the particular fistula being treated. This may involvea pre-implantation measurement step where one or more dimensions of afistula such as the fistula tract length, diameter, etc., are determinedIn some cases, a graft body may need to be altered before or duringimplantation, for example, trimmed lengthwise to suit a particularfistula tract length. The loosely retained first cap 204 may then beattached to first plug body end 202 using additional suture material oranother suitable attachment means (e.g., stapling or bonding with anadhesive). Next, the dried plug body 201 may be at least partiallyhydrated (optional), and then deployed by passing the second plug bodyend 203 through a fistula opening on the rectal side and advancing ittoward the fistula opening on the vaginal side. This step may befacilitated by receiving the fistula plug over an emplaced guidewire210. The plug body 201 may then be advanced until the first cap 204contacts portions of the rectal cavity wall adjacent to the fistulaopening. Bonding agents, sutures, mechanical fasteners and/or othersuitable securing means may be used in certain embodiments to maintainor at least help maintain this contact. Plug body 201 can be advancedthrough the fistula tract in any suitable manner, and in some forms, ispulled through the tract, e.g., by pulling on suture strand 209. Suturestrand 209 may then be passed through apertures in the second cap 205,and the second cap 205 may be threaded onto the guidewire (if present).In advantageous embodiments, the plug body 201 will be sized so that,upon being pulled into position (i.e., with the first cap 204 contactingthe rectal cavity wall), the second plug body end 203 will be generallyflush with the tissue surrounding the fistula opening on the vaginalside. Alternatively, the second plug body end 203, when pulled intoposition, will extend beyond the fistula opening on the vaginal side,and in this case, can be trimmed as desired (e.g., to be generally flushwith the vaginal cavity wall). The second cap 205 is then attached tothe second plug body end 203. If present, the guidewire can then beremoved, and suture strand 209 can be trimmed as necessary.

In alternative embodiments, suture material can be passed throughcentral lumen 206 and directly bonded to one or more caps. This suturematerial can provide means for adjusting graft body positioning duringand/or after deployment, and potentially also provide means foranchoring the plug body 201 during a deployment step, for example, bysuturing plug body 201 to patient tissue at or adjacent to a fistulaopening.

Passages occurring in a graft body, such as those depicted in FIG. 12,may be formed in any suitable manner. In some embodiments, passages canbe created in a graft body after the graft body is formed, e.g., after acast collagenous material is dried to form a coherent body. In someembodiments, at least part of the formation of some or all of thepassages in a graft body occurs during formation of the graft body.Illustratively, an inventive method can include a step where a passageis initially provided in a hydrated material mass, e.g., by displacing avolume of material in the mass. Then, with the passages present in thehydrated material mass, the mass can be subjected to suitable dryingconditions (e.g., a lyophilization step) to cause or allow the passagesto be retained in the dried graft body. It should be noted that ahydrated material in such processes (e.g., a reconstituted ornaturally-derived collagenous material) can have a level of hydrationincluding full or partial hydration, and in this regard, a dryingprocess can be used to lower starting material hydration to any suitablelevel including substantially dehydrated. Also, displacing a volume ofmaterial in a hydrated mass of material to create a passage can beaccomplished in a variety of manners, and in certain aspects, involvesforcing or otherwise introducing an implement or othermaterial-displacing object (e.g., a cannulated or non-cannulated needle)into the mass. Other suitable material-displacing objects can beselected according to the type of passage desired.

These and other inventive graft body formation methods can involvemanipulating graft material within a mold or form. It should be notedthat the graft material may or may not be hydrated when placed in, on,around, etc. a mold or form. In some methods, a substantially dry ECMmaterial (e.g., a powder or sheet material) can be placed in a mold andthen suitably hydrated for further processing. In other methods, ahydrated starting material is placed in and/or on a mold or formingstructure for further processing. For example, one or more hydratedsheets of ECM material can be applied to a form, e.g., wrapped at leastpartially around a mandrel so that portions of the sheet(s) overlap.Then, the one or more sheets can be dried, and in some embodiments,dried while under compression, to form a unitary graft construct. Insome modes of operation, a hydrated graft material is provided within asingle- or multiple-part mold having a plurality of apertures or holesextending through a wall of the mold, thereby providing access to themold interior from an external location. These apertures can serve toenhance drying of a hydrated material during a processing step and inprocesses exerting vacuum pressure at these apertures, can promoteand/or facilitate formation of surface protuberances on the graftmaterial as portions of the same are drawn toward the apertures whileunder vacuum. In one aspect, an amount of ECM material is retained insuch a mold, and needles or other material-displacing objects areinserted through some or all of the mold apertures and a distance intothe ECM material, thereby displacing volumes of the ECM material. Thiscan be performed when the graft material is hydrated, partially hydratedor dehydrated. In some forms, with needles inserted in a hydrated ECMmaterial and providing passages therein, the material is subjected toconditions (e.g., freezing and/or dehydrating conditions) which, aloneor in combination with one or more other conditions, cause or allow thepassages to be generally retained in the ECM material after the needlesare removed.

In some embodiments, one or more sheets of hydrated ECM material aresuitably wrapped and/or randomly packed around a mandrel, and then amold having a plurality of holes extending through a wall of the mold isplaced around the material-covered mandrel, for example, so that anamount of pressure is placed on the ECM material. The mandrel can thenoptionally be removed. Thereafter, needles or other material-displacingobjects are inserted through some or all of the holes and at leastpartially through the ECM material, thereby displacing volumes of theECM material. The ECM material is then at least partially dried. In someaspects, a suitable lyophilization technique is employed, e.g., one withor without a pre-freezing step as described herein. In these or otherdrying methods in which needles or other penetrating elements are to beleft within the mass during drying, these elements can optionally beprovided with a plurality of apertures or holes or can otherwise besufficiently porous to facilitate the drying operation by allowing thepassage of hydrate from the wet mass. In one embodiment, a hydrated ECMmaterial with emplaced needles can be subjected to freezing conditionsso that the material and any contained hydrate become substantiallyfrozen. Thereafter, the needles can be removed from the ECM material,and the remaining construct (with the frozen material passagessubstantially retaining their shape) can be placed under a vacuum sothat the frozen hydrant sublimes from the material, thereby resulting ina dry graft construct with retained passages therein.

In other modes of operation, passage-forming structures can beincorporated integrally into a mold so that passageways are formed uponintroducing the starting material in and/or on the mold. In theseaspects, the passage-forming structures can be part of the mold (e.g.,extend from a surface of the mold), or they can be separate objectsattached or otherwise coupled to the mold, to provide the desiredpassage or passages through the ultimately-formed graft body.

Although not necessary to broader aspects of the invention, in someembodiments, the formation of such a graft construct comprises wrappingone or more sheets of hydrated graft material around a mandrel a numberof times. The resulting roll of graft material is then introduced into amold, and the mandrel is removed (optional), e.g., before or afterapplying the mold. Thereafter, multiple material-displacing objects suchas but not limited to needles are forced through apertures in the moldand into the hydrated graft material, and the material is subjected toone or more drying techniques such as a lyophilization process. In otheraspects, the formation of such a graft construct includes placing aflowable graft material into a mold and then subjecting the graftmaterial to further processing. For example, a flowable ECM materialmass, such as a gel, paste or putty, potentially incorporating aparticulate ECM material, can be placed into a mold, and then withvolumes of material displaced in the mass (e.g., by penetratingneedles), the ECM material can be dried or otherwise caused to form anintegral piece to provide a graft body having passages therein.Illustratively, each of the passages can be provided by forcing a singleobject through the material mass, or alternatively, where a mandrel isleft in place to form a longitudinal lumen, by forcing two objects intothe mass and toward one another from opposite directions until they abutthe mandrel. The mass can then be processed to a solid graft body asdiscussed herein.

In some aspects of the invention, where multiple fistulas are present,multiple grafts may be inserted until all fistula tracts have beenclosed. In the case of a complex fistula, for instance a horseshoefistula, there may be one primary opening and two or more tracts leadingfrom that opening. In this instance, a graft may be configured with oneproximal end (e.g., a larger diameter end), and two distal ends (e.g.,smaller diameter ends). Desirably, accurate identification of allfistula tracts and the primary opening is facilitated by firstperforming fistuloscopy. Once the entire tract has been identified andcleaned out, each tail may be pulled through the primary opening intoeach fistula in turn, desirably using a fistulascope or an instrumentpassed through the instrument channel of a scope. Adequate force may beapplied to the tail to ensure that the proximal end of the graft body isfirmly secured in the primary opening and/or the cap attached to theproximal end of the graft body contacts the alimentary canal walladjacent to the primary opening. The proximal end of the graft and/oreach of the tails may be further secured by any of the methods describedabove.

The closure of fistulas with the grafts and methods of the presentinvention results in minimal cutting or piercing of tissue (if any),sphincter damage, and incontinence. In addition, the current inventionsimplifies the implantation procedure and prevents dislodgement of thegrafts.

All publications and patent applications cited in this specification arehereby incorporated by reference in their entirety, as if eachindividual publication or patent application were specifically andindividually indicated to be incorporated by reference. Further, anytheory, mechanism of operation, proof, or finding stated herein is meantto further enhance understanding of the present invention, and is notintended to limit the present invention in any way to such theory,mechanism of operation, proof, or finding. While the invention has beenillustrated and described in detail in the drawings and foregoingdescription, the same is to be considered as illustrative and notrestrictive in character, it being understood that only selectedembodiments have been shown and described and that all equivalents,changes, and modifications that come within the spirit of the inventionsas defined herein or by the following claims are desired to beprotected.

1-20. (canceled)
 21. A fistula graft for treating a fistula having anopening in a first tissue wall, an opening in a second tissue wall, anda fistula tract extending therebetween, the fistula graft comprising: afirst cap; and an elongate graft body having a first end attached to thefirst cap and a second end, the elongate graft body comprisingremodelable material selected from the group consisting of a cadavericmaterial from a human donor and a heterograft material from a non-humandonor, wherein the elongate graft body further comprises progenitorcells.
 2. The fistula graft of claim 1, further comprising: a gaskethaving a lumen, wherein the elongate graft body extends through thelumen and wherein the gasket is positioned against the first cap. 22.The fistula graft of claim 21, wherein the elongate graft body comprisesa rolled or folded intact, acellular sheet of remodelable material thatpromotes cellular invasion and ingrowth within the acellular sheet andreconstruction of host tissue within the acellular sheet.
 23. Thefistula graft of claim 21, wherein the graft body comprises aremodelable material selected from the group consisting of submucosa,renal capsule membrane, dermal collagen, dura mater, pericardium,serosa, peritoneum, basement membrane layers, and liver basementmembrane.
 24. The fistula graft of claim 23, wherein the remodelablematerial is selected from the group consisting of submucosa and dermalcollagen.
 25. The fistula graft of claim 21, wherein the first cap isintegral with the elongate graft body and formed from the same materialas the elongate graft body.
 26. The fistula graft of claim 21, whereinthe first cap is affixed to the elongate graft body in a non-permanentmanner.
 27. The fistula graft of claim 26, wherein the first cap isaffixed to the elongate graft body by a suture.
 28. The fistula graft ofclaim 21, wherein the first end of the elongate graft body is largerthan the second end and wherein the elongate graft body comprises ataper between the first end and the second end.
 29. The fistula graft ofclaim 21, wherein the first cap comprises an absorbable material. 30.The fistula graft of claim 21, wherein the gasket comprises and intact,acellular sheet of remodelable material that promotes cellular invasionand ingrowth within the acellular sheet and reconstruction of hosttissue within the acellular sheet.
 31. The fistula graft of claim 21,wherein the remodelable material is submucosa.
 32. The fistula graft ofclaim 21, wherein the gasket attaches to the first cap by a suture. 33.The fistula graft of claim 21, wherein the first cap comprises abioresorbable polymer.
 34. The fistula graft of claim 21, wherein theremodelable material comprises stacked extracellular matrix segments.35. A fistula graft for treating a fistula having an opening in a firsttissue wall, an opening in a second tissue wall, and a fistula tractextending therebetween, the fistula graft comprising: an elongate graftbody having a first end and a second end, the elongate graft bodycomprising remodelable material selected from the group consisting of acadaveric material from a human donor and a heterograft material from anon-human donor, wherein the elongate graft body further comprisesprogenitor cells.
 36. A fistula graft for treating a fistula having anopening in a first tissue wall, an opening in a second tissue wall, anda fistula tract extending therebetween, the fistula graft comprising: afirst cap; and an elongate graft body having a first end attached to thefirst cap and a second end, the elongate graft body comprisingremodelable material selected from the group consisting of a cadavericmaterial from a human donor and a heterograft material from a non-humandonor, wherein the first cap attaches to the first end of the elongategraft body in a manner resulting in detachment and release of the firstcap from the elongate graft body following implantation of the fistulagraft in the fistula and wherein the elongate graft body furthercomprises progenitor cells.
 37. The fistula graft of claim 36, whereinthe remodelable material is selected from the group consisting ofsubmucosa and dermal collagen.
 38. The fistula graft of claim 36,wherein the first cap comprises an absorbable material.
 39. The fistulagraft of claim 36, wherein the first cap comprises a synthetic polymericmaterial.
 40. The fistula graft of claim 36, wherein a bioabsorbablesuture attaches the first end of the elongate graft body to the firstcap and wherein the attachment is such that the cap detaches from theelongate graft body upon absorption of the suture.